ICM1

ICM1 (PF3D7_1231400) is a multipass membrane protein that acts downstream of PKG to mobilize calcium from intracellular stores, coupling PKG signaling to the calcium-dependent transitions of the Plasmodium life cycle (PMID:33762339). It physically associates with PKG across asexual blood stages and transmission stages of both P. falciparum and P. berghei, and is itself phosphorylated at multiple sites in a PKG-activity-dependent manner, placing it as a direct effector within the PKG signaling module (PMID:33762339). Functionally, conditional depletion of ICM1 collapses intracellular calcium mobilization: in P. berghei this blocks gametogenesis, while in P. falciparum it impairs merozoite egress and abolishes invasion (PMID:33762339). This calcium-mobilizing role is selective rather than global to egress, since ICM1 loss in P. falciparum does not prevent exoneme exocytosis of SUB1 into the parasitophorous vacuole, defining a boundary on the processes it controls (PMID:42113900). Beyond its membership in the PKG-ICM1 module and its role in calcium release, the transport or channel activity implied by its sequence has not been directly characterized in the available corpus.

1. 2021 Medium

   Establishing whether PKG operates through a dedicated membrane effector was unknown; identifying ICM1 as a tight PKG-associated multipass membrane protein defined a physical PKG signaling module conserved across species and life-cycle stages.

   Evidence Reciprocal co-immunoprecipitation and interaction proteomics in asexual and transmission stages of P. falciparum and P. berghei

   PMID:33762339

   Open questions at the time

   • Interaction shown by co-IP/proteomics in a single lab without structural mapping of the interface
   • Whether the association is direct or bridged by other complex members is not resolved
   • The transporter/channel activity implied by homology was not tested biochemically
2. 2021 Medium

   Whether ICM1 is a PKG substrate or merely a binding partner was open; PKG-dependent phosphorylation placed ICM1 as a regulated node within the pathway.

   Evidence Phosphoproteomic mass spectrometry comparing wild-type and PKG-inhibited parasites

   PMID:33762339

   Open questions at the time

   • PKG-dependency established by chemical inhibition rather than direct kinase reconstitution
   • Functional consequence of the specific phosphosites was not tested by phosphomutants
3. 2021 High

   The physiological output of the PKG-ICM1 association was unknown; conditional depletion showed ICM1 is required for intracellular calcium mobilization driving gametogenesis, egress, and invasion.

   Evidence Stage-specific conditional depletion with calcium imaging in P. berghei (gametogenesis) and calcium, egress, and invasion assays in P. falciparum

   PMID:33762339

   Open questions at the time

   • Whether ICM1 itself transports calcium or gates another channel was not directly demonstrated
   • The intracellular store(s) mobilized were not molecularly resolved
4. 2024 Medium

   Whether ICM1-dependent calcium release governs all egress-associated secretion was open; ICM1 loss did not block SUB1 exoneme exocytosis, defining a functional boundary for ICM1 activity.

   Evidence Conditional knockout with fluorescent exocytosis reporter and SUB1 localization in P. falciparum

   PMID:42113900

   Open questions at the time

   • Negative finding from a single study using one exocytosis readout
   • The full set of calcium-dependent secretory events that do require ICM1 is not delineated
5. 2024 Low

   The subcellular site of PKG-ICM1 action was unclear; an ER-associated PKG sub-population possibly anchored by ICM1 was inferred, pointing to the ER as a candidate signaling locus.

   Evidence Inference in discussion citing prior interaction work; no new direct experiment for this claim in P. falciparum

   PMID:38935780

   Open questions at the time

   • Claim is an inference from cited prior work, not a new direct experiment; ICM1 ER localization not independently demonstrated here
   • Direct evidence that ICM1 anchors PKG to the ER is absent

• Whether ICM1 is itself the calcium-transporting/channel entity or a regulatory scaffold that gates a distinct store-release machinery remains unresolved.
• No reconstitution or electrophysiological demonstration of ICM1 transport/channel activity
• No structural model of ICM1 or its PKG interface
• The identity of the calcium store and any partner transporters are uncharacterized